Epigenetic events are believed to affect many steps in tumour development, therefore, understanding epigenetic changes associated with cancer onset, progression and metastasis is fundamental to improving our abilities to successfully prevent, diagnose and treat cancer. Various dietary and environmental factors are suspected to be implicated in the development of a wide range of human cancers by eliciting epigenetic changes, however, the contribution of epigenetic mechanisms (such as DNA methylation and chromatin modifications) and the precise targets of epigenetic alterations during cancer development are largely unknown. Major obstacle in establishing relationship between epigenetic changes and dietary and environmental factors in cancer is the fact that case-control studies tend to be too small and to lack statistical power to identify the interactions between epigenetic changes and environmental and lifestyle factors. Long-term objectives of this study will be to measure the contribution of epigenetic events induced by dietary and environmental factors to cancer development using large sample size of several thousands subjects. This study will take advantage of large case-control studies on lung and upper-aero-digestive tract (UADT) cancers in Europe whose recruitment has been recently completed. This large sample size together with quantitative measurement of changes in DNA methylation and chromatin modifications will ensure that epigenetic events with even moderate effects will be positively identified, whereas false positive results will likely be very limited. The specific aims of this study are: (1) To analyze DNA methylation profiles in lung and UADT cancers and their association with dietary and environmental exposures using large case-control studies, (2) to analyze the patterns of histone modifications and to profile their genomic locations in selected lung and UADT cancers and their association with dietary and environmental exposures, and (3) to compare the profile of DNA methylation and histone modifications between cases and controls and assess whether it can be a cancer susceptibility marker. Together, these studies will allow assessment of the involvement of epigenetic events in human cancers caused by established risk factors (e.g. tobacco smoking, diet and environmental exposures) as well as suspected risk factors in the diet and environment, providing a powerful tool in the development of strategies for risk assessment, molecular diagnostics and cancer prevention. [unreadable] [unreadable] [unreadable]